New crystal form of GLP-1 receptor agonist, preparation method, pharmaceutical composition and application thereof

Abstract

The invention relates to a novel crystal form of a GLP-1 receptor agonist, a preparation method, a pharmaceutical composition and application thereof. In particular, the GLP-1 receptor agonist is a compound I, i.e., (S)-2-((4-(6-((2-fluoro-4-(oxetan-3-yl) benzyl) oxy) pyridin-2-yl) piperidin-1-yl) methyl)-1-(oxetan-2-yl methyl)-1H-benzo [d] imidazole-6-carboxylic acid.

Description

New crystal form of GLP-1 receptor agonist, preparation method thereof, pharmaceutical composition and use thereof Technical Field

[0001] The present application relates to a new crystal form of a GLP-1 receptor agonist and a preparation method thereof, and also relates to a pharmaceutical composition comprising the crystal form, and the use of the crystal form and the pharmaceutical composition for treating and / or preventing GLP-1 receptor-mediated diseases or related conditions. Background Art

[0002] Diabetes mellitus is a chronic, complex disease characterized by impaired glucose metabolism, caused by absolute or relative insulin deficiency or decreased insulin sensitivity in target cells. It is categorized into type 1 and type 2 diabetes. Type 2 diabetes is an adult-onset endocrine disease characterized by chronic hyperglycemia due to insulin resistance and / or insulin secretion defects. Type 2 diabetes accounts for over 90% of all diabetic patients.

[0003] Insulin and GLP-1 receptor agonists are among the most effective treatments for type 2 diabetes. Insulin preparations remain the most commonly used diabetes medication worldwide, with approximately 30-40% of patients with type 2 diabetes ultimately requiring insulin. GLP-1 preparations primarily include exenatide, liraglutide, and semaglutide. However, current insulin and GLP-1 preparations are primarily peptide-based and injectable. Even oral semaglutide has numerous limitations. Therefore, further development of small-molecule GLP-1 receptor agonists is warranted.

[0004] Other conditions associated with type 2 diabetes include diabetic nephropathy, diabetic eye complications (diabetic retinopathy, diabetes-related uveitis, diabetic cataracts), diabetic foot, diabetic cardiovascular complications, diabetic cerebrovascular disease, diabetic neuropathy, obesity, and hypertension.

[0005] GLP-1 receptor agonists are highly promising drugs, and most are currently administered via injection. The development of oral small-molecule GLP-1 receptor agonists, which can improve patient compliance, is a key development trend for GLP-1 receptor agonists.

[0006] Summary of the Invention

[0007] (S)-2-((4-(6-((2-fluoro-4-(oxetan-3-yl)benzyl)oxy)pyridin-2-yl)piperidin-1-yl)methyl)-1-(oxetan-2-ylmethyl)-1H-benzo[d]imidazole-6-carboxylic acid (C 33 H 35FN4O5) is a small molecule GLP-1 receptor agonist, also referred to as Compound I in the specification and claims of this application, and has the following structure:

[0008] The inventors have prepared compound I and have shown through research that:

[0009] (1) It is in an amorphous form, and its X-ray powder diffraction (XRPD) pattern is shown in Figure 1-1;

[0010] (2) In a differential scanning calorimetry (DSC) test, no melting point was detected until the temperature was raised to 300°C; its DSC spectrum is shown in Figure 1-2; and

[0011] (3) In the thermogravimetric analysis (TGA) test, the weight loss was 4.66% when the temperature was raised to 160°C; its TGA spectrum is shown in Figures 1-3.

[0012] One object of the present invention is to further provide a new crystalline form of Compound I.

[0013] Therefore, in one aspect, the present invention provides crystalline forms of Compound 1, including Form A, Form B, Form C, Form D, Form E, Form F, Form G, Form H, Form Ix, Form J, Form K, Form L, Form M, Form N, Form O and Form P, preferably Form A and Form G, more preferably Form G, as described below.

[0014] The crystalline form of Compound I of the present invention has good physicochemical properties, such as low hygroscopicity, good physicochemical stability (thermodynamic stability, solid-state stability, high temperature resistance, high humidity resistance and / or high pressure resistance), and has the potential to have good drugability and / or bioavailability.

[0015] In another aspect, the present invention provides a process for preparing a crystalline form of Compound I of the present invention.

[0016] In another aspect, the pharmaceutical composition of the present invention comprises the crystalline form of Compound I of the present invention, preferably the crystalline form A or crystalline form G, more preferably the crystalline form G.

[0017] In another aspect, the present invention provides a crystalline form of Compound I of the present invention, preferably the crystalline form A or crystalline form G, more preferably the crystalline form G, or a pharmaceutical composition of the present invention, which is used to treat and / or prevent GLP-1 receptor-mediated diseases and related conditions.

[0018] In another aspect, the present invention provides a crystalline form of Compound I of the present invention, preferably the crystalline form A or crystalline form G, more preferably the crystalline form G, or a pharmaceutical composition of the present invention, for use in the preparation of a medicament for treating and / or preventing GLP-1 receptor-mediated diseases or related conditions.

[0019] In another aspect, the present invention provides a method for treating and / or preventing GLP-1 receptor-mediated diseases or related conditions, comprising administering to an individual in need thereof an effective amount of a crystalline form of Compound I of the present invention, preferably Form A or Form G, more preferably Form G, or a pharmaceutical composition of the present invention.

[0020] In some embodiments, the GLP-1 receptor mediated disease or related condition is selected from the group consisting of diabetes, hyperglycemia, insulin resistance, glucose intolerance, diabetic nephropathy, diabetic neuropathy, diabetic retinopathy, adipocyte dysfunction, obesity, non-alcoholic fatty liver disease, dyslipidemia, and hyperinsulinemia. In some embodiments, the diabetes is selected from the group consisting of type 1 diabetes (T1D) and / or type 2 diabetes (T2DM), idiopathic T1D, early-onset T2DM, latent autoimmune diabetes, atypical diabetes of the juvenile, and gestational diabetes. BRIEF DESCRIPTION OF THE DRAWINGS

[0021] Figure 1-1 is the XRPD spectrum of the amorphous form of Compound 1; Figure 1-2 is the DSC spectrum of the amorphous form; and Figure 1-3 is the TGA spectrum of the amorphous form.

[0022] Figure 2-1 is the XRPD spectrum of Compound I Form A; Figure 2-2 is the DSC spectrum of the Form A; Figure 2-3 is the TGA spectrum of the Form A; Figure 2-4 is the 1 H NMR spectrum; Figure 2-5 is the DVS spectrum of the crystalline form A.

[0023] Figure 3-1 is the XRPD spectrum of Form G of Compound I; Figure 3-2 is the DSC spectrum of Form G; Figure 3-3 is the TGA spectrum of Form G; Figure 3-4 is the 1 H NMR spectrum; Figure 3-5 is the DVS spectrum of the crystalline form G.

[0024] Figure 4-1 is an XRPD spectrum of Form C of Compound I; Figure 4-2 is a DSC spectrum of Form C; Figure 4-3 is a TGA spectrum of Form C; Figure 4-4 is a 1 H NMR spectrum.

[0025] Figure 5-1 is the XRPD spectrum of Form D of Compound I; Figure 5-2 is the DSC spectrum of Form D; Figure 5-3 is the TGA spectrum of Form D; Figure 5-4 is the 1 H NMR spectrum.

[0026] Figure 6-1 is an XRPD spectrum of Form E of Compound I; Figure 6-2 is a DSC spectrum of Form E; Figure 6-3 is a TGA spectrum of Form E; Figure 6-4 is a 1 H NMR spectrum.

[0027] FIG7-1 is an XRPD spectrum of Compound I Form Ix; FIG7-2 is a DSC spectrum of the Form Ix; FIG7-3 is a TGA spectrum of the Form Ix; FIG7-4 is a TGA spectrum of the Form Ix 1 H NMR spectrum.

[0028] Figure 8-1 is the XRPD spectrum of Form J of Compound I; Figure 8-2 is the DSC spectrum of Form J; Figure 8-3 is the TGA spectrum of Form J; Figure 8-4 is the 1 H NMR spectrum.

[0029] Figure 9-1 is an XRPD spectrum of Compound I Form K; Figure 9-2 is a DSC spectrum of the Form K; Figure 9-3 is a TGA spectrum of the Form K; Figure 9-4 is a 1 H NMR spectrum.

[0030] Figure 10-1 is an XRPD spectrum of Form L of Compound I; Figure 10-2 is a DSC spectrum of Form L; Figure 10-3 is a TGA spectrum of Form L; Figure 10-4 is a 1 H NMR spectrum.

[0031] Figure 11-1 is an XRPD spectrum of Compound I Form M; Figure 11-2 is a DSC spectrum of the Form M; Figure 11-3 is a TGA spectrum of the Form M; Figure 11-4 is a 1 H NMR spectrum.

[0032] Figure 12-1 is an XRPD spectrum of Compound I Form N; Figure 12-2 is a DSC spectrum of the Form N; Figure 12-3 is a TGA spectrum of the Form N; Figure 12-4 is a 1 H NMR spectrum.

[0033] Figure 13-1 is an XRPD spectrum of Compound I Crystal Form O; Figure 13-2 is a DSC spectrum of the Crystal Form O; Figure 13-3 is a TGA spectrum of the Crystal Form O; Figure 13-4 is a 1H NMR spectrum.

[0034] Figure 14 is an XRPD spectrum of Compound 1 Form B.

[0035] Figure 15 is an XRPD spectrum of Compound 1 Form H.

[0036] Figure 16 is an XRPD spectrum of Compound 1 Form F.

[0037] Figure 17 is an XRPD spectrum of Compound I Form P. DETAILED DESCRIPTION

[0038] The present invention is further explained below. It should be understood that the terms are intended to describe rather than limit the present invention.

[0039] definition

[0040] Unless otherwise stated, all technical terms and scientific terms used herein have the same meaning as those generally understood by those skilled in the art to which the present invention belongs. If there is a contradiction, the definition herein shall prevail. When a certain amount, concentration or other value or parameter is expressed in the form of a range, a preferred range or a preferred upper numerical limit and a preferred lower numerical limit, it should be understood that it is equivalent to specifically revealing any range by combining any pair of upper range limits or preferred numerical values ​​with any lower range limit or preferred numerical value. Unless otherwise stated, the numerical ranges listed herein are intended to include the endpoints of the range and all integers and fractions (decimals) within the range.

[0041] The term "about" when used in conjunction with a numerical variable generally means that the value of that variable and all values ​​of that variable are within experimental error (e.g., within a 95% confidence interval for the mean) or within a range of ±20%, ±10%, ±5%, or ±2% of the stated value.

[0042] As used herein, the term "about" when describing XRPD diffraction angles means that one of ordinary skill in the art considers to be within an acceptable standard error of the stated value, for example, ±0.05, ±0.10, ±0.20, ±0.30, ±1, ±2, or ±3, etc.

[0043] The term "comprising" or its synonyms "including," "containing," and "having" are open ended and do not exclude additional unrecited elements, steps, or ingredients. The expression "consisting of excludes any element, step, or ingredient not specified. The term "consisting essentially of" means that the scope is limited to the specified elements, steps, or ingredients, plus any optional elements, steps, or ingredients that do not materially affect the basic and novel characteristics of the claimed subject matter. It should be understood that the terms "comprising," "including," and similar terms encompass the terms "consisting essentially of" and "consisting of."

[0044] As used herein, the term "optional" or "optionally" means that the subsequently described event or circumstance may or may not occur, and that the description includes both occurring and not occurring.

[0045] Unless otherwise indicated, percentages, parts, etc. herein are by weight.

[0046] As used herein, the term "crystalline form" or "crystal" refers to any solid material that exhibits a three-dimensional ordering, as opposed to amorphous solid material, which produces a characteristic XRPD pattern with well-defined peaks.

[0047] As used herein, the term "X-ray powder diffraction pattern" or "XRPD pattern" refers to an experimentally observed diffraction pattern or a parameter, data or value derived therefrom. An XRPD pattern is typically characterized by peak positions (abscissa) and / or peak intensities (ordinate).

[0048] As used herein, the term "diffraction angle" or "2θ" refers to the peak position expressed in degrees (°) based on the setup in the X-ray diffraction experiment, and is generally the unit of the abscissa in the diffraction pattern. If the reflection is diffracted when the incident beam forms an angle θ with a certain lattice plane, the experimental setup requires that the reflected beam be recorded at an angle of 2θ. It should be understood that the specific 2θ value of a specific crystalline form mentioned herein is intended to represent the 2θ value (expressed in degrees) measured using the X-ray diffraction experimental conditions described herein. For example, as described herein, using Cu-Kα ( The XRPD patterns herein are preferably collected on a Bruker D8 Advance (Bruker, Germany) X-ray powder diffraction analyzer.

[0049] As used herein, the term "substantially the same" or "substantially as shown in Figure X" with respect to X-ray diffraction peaks means that variations in representative peak positions and intensities are taken into account. For example, one skilled in the art will appreciate that peak positions (2θ) will exhibit some variation, typically as much as 0.1 to 0.2 degrees, and that the instrument used to measure diffraction will also introduce some variation. In addition, one skilled in the art will appreciate that relative peak intensities will vary due to instrumental variations, as well as the degree of crystallinity, preferred orientation, the surface of the sample being prepared, and other factors known to one skilled in the art.

[0050] Similarly, as used herein, "substantially as shown in Figure X" with respect to DSC and TGA patterns is also intended to encompass variations associated with these analytical techniques known to those skilled in the art. For example, for well-defined peaks in a DSC pattern, there will typically be variations of up to ±0.2°C, and even greater (e.g., up to ±1°C) for broad peaks.

[0051] The NMR spectra in this application were preferably collected on a Bruker AVANCE-III or Bruker AVANCE NEO (Bruker, GER) NMR spectrometer, using MeOD-d4 as the solvent unless otherwise stated.

[0052] As used herein, the term "solvent" or "good solvent" means a solvent in which Compound 1 is soluble or has a relatively higher solubility. As used herein, the term "anti-solvent" means a solvent in which Compound 1 is insoluble or substantially insoluble or has a relatively lower solubility. Herein, the terms "solvent" or "good solvent" and "anti-solvent" may also be relative and do not indicate the absolute solubility of Compound 1 therein. The same solvent may act as a good solvent in some cases and as an anti-solvent in other cases.

[0053] As used herein, numerical ranges (e.g., "1 to 10") and subranges thereof (e.g., "2 to 10," "2 to 6," "3 to 10," etc.) encompass any number (e.g., 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10) in the stated numerical range.

[0054] As used herein, the term "room temperature" refers to 20°C ± 5°C.

[0055] I. Crystalline Forms of Compound 1

[0056] The present invention provides crystalline forms of Compound I, including Form A, Form B, Form C, Form D, Form E, Form F, Form G, Form H, Form Ix, Form J, Form K, Form L, Form M, Form N, Form O, and Form P, as described below. Preferred crystalline forms are Form A and Form G, and Form G is more preferred.

[0057] The present invention also provides a method for preparing the crystal form, including but not limited to slow volatilization, suspension stirring at low temperature (e.g., 4-8°C), suspension stirring at room temperature, suspension stirring at high temperature (e.g., 50°C), anti-solvent addition, anti-antisolvent addition, cooling crystallization, gas-liquid diffusion, gas-solid diffusion, water vapor stress, polymer induction, grinding, rotary evaporation and cyclic heating and cooling.

[0058] i.Crystal Form A

[0059] The present invention provides a crystalline form A of compound I, characterized in that the X-ray powder diffraction (XRPD) pattern of the crystalline form A includes diffraction peaks at the following diffraction angles (2θ): approximately 4.97±0.2°, 11.74±0.2°, 13.27±0.2°, 21.04±0.2° and 24.06±0.2°.

[0060] Alternatively or further, the crystalline form A has any one, two or all of the following characteristics:

[0061] (1) The differential scanning calorimetry (DSC) spectrum of the crystalline form A has a single endothermic peak at a peak value of approximately 177.8°C ± 3.0°C;

[0062] (2) Form A loses approximately 0.037% weight during heating to approximately 150°C ± 3°C, as measured using thermogravimetric analysis (TGA);

[0063] (3) the crystal form A 1 The H NMR spectrum is basically as shown in Figures 2-4.

[0064] In some preferred embodiments, the XRPD pattern of the crystalline form A further comprises diffraction peaks at any one, multiple or all of the following diffraction angles (2θ): about 15.88±0.2°, 16.26±0.2°, 16.44±0.2°, 18.43±0.2°, 19.17±0.2°, 19.48±0.2°, 19.65±0.2°, 19.89±0.2°, 20.11±0.2°, 20.67±0.2°, 21.27±0.2°, 22.81±0.2° and 23.4±0.2°.

[0065] In some preferred embodiments, the XRPD pattern of the crystalline form A further comprises diffraction peaks at any one, multiple or all of the following diffraction angles (2θ): about 9.99±0.2°, 17.65±0.2°, 20.32±0.2°, 24.26±0.2°, 24.76±0.2°, 25.79±0.2°, 26.75±0.2°, 27.47±0.2°, 28.19±0.2°, 29.38±0.2° and 29.91±0.2°.

[0066] In some preferred embodiments, the DSC spectrum of the crystalline form A is substantially as shown in Figure 2-2.

[0067] In some preferred embodiments, the TGA spectrum of the crystalline form A is substantially as shown in Figures 2-3.

[0068] In some more preferred embodiments, the XRPD pattern of the crystalline form A includes a diffraction peak at a diffraction angle (2θ) substantially the same as that shown in Figure 2-1, and further more preferably, the XRPD pattern of the crystalline form A is as shown in Figure 2-1.

[0069] The TGA weight loss of the crystal form A is small, and the 1The H NMR spectrum shows no obvious residual solvent. In some embodiments, the crystalline form A is not a solvate. More preferably, the crystalline form A is an anhydrate.

[0070] In some embodiments, the crystalline Form A has a melting point greater than about 170°C.

[0071] In some embodiments, no crystalline form change is observed in the crystalline Form A after drying at about 50° C. for 3 hours.

[0072] The crystal form A has good solid-state stability, high-temperature stability, high-humidity stability and pressure stability, as well as low hygroscopicity.

[0073] In another aspect, the present invention also provides a method for preparing the crystalline form A, comprising stirring a suspension of the amorphous form of Compound 1 in acetone:H2O (e.g., about 1:4 v:v) at an elevated temperature to obtain the crystalline form A as a solid precipitate.

[0074] In some embodiments, the elevated temperature is a temperature of about 40-70°C, such as a temperature of about 45-65°C or about 50-60°C, preferably about 50°C.

[0075] In some embodiments, the stirring may be performed for a suitable period of time, such as about 1-2 days.

[0076] ii. Form G

[0077] The present invention also provides a crystalline form G of compound I, characterized in that the XRPD spectrum of the crystalline form G includes diffraction peaks at the following diffraction angles (2θ): approximately 4.99±0.2°, 10.05±0.2°, 16.99±0.2°, 19.21±0.2° and 20.28±0.2°.

[0078] Alternatively or further, the crystalline form G has any one, two or all of the following characteristics:

[0079] (1) The DSC spectrum of Form G has a single endothermic peak at approximately 188.3°C ± 3.0°C;

[0080] (2) Form G loses about 0.494% of its weight during heating to about 180°C ± 3°C, as measured using TGA.

[0081] In some preferred embodiments, the XRPD pattern of the crystalline form G further includes diffraction peaks at any one, multiple or all of the following diffraction angles (2θ): about 12.33±0.2°, 15.84±0.2°, 17.34±0.2°, 17.59±0.2°, 20.67±0.2°, 21.68±0.2° and 26.59±0.2°.

[0082] In some preferred embodiments, the XRPD pattern of the crystalline form G further includes diffraction peaks at any one, multiple or all of the following diffraction angles (2θ): about 12.62±0.2°, 15.00±0.2°, 18.30±0.2°, 23.88±0.2°, 24.72±0.2°, 29.12±0.2° and 33.76±0.2°.

[0083] In some preferred embodiments, the DSC spectrum of the crystalline form G is substantially as shown in Figure 3-2.

[0084] In some preferred embodiments, the TGA spectrum of the crystalline form G is substantially as shown in Figure 3-3.

[0085] In some more preferred embodiments, the XRPD pattern of the crystalline form G includes a diffraction peak at a diffraction angle (2θ) substantially the same as that shown in Figure 3-1, and further more preferably, the XRPD pattern of the crystalline form G is as shown in Figure 3-1.

[0086] The TGA weight loss of the crystal form G is small. 1 H NMR analysis showed no significant residual solvent. In some embodiments, the crystalline Form G is not a solvate. More preferably, the crystalline Form G is an anhydrate.

[0087] In some embodiments, the Form G has a melting point greater than about 170°C.

[0088] The crystalline form G is a more thermodynamically stable crystalline form at room temperature and 50° C. Suspension competition experiments of crystalline form A and crystalline form G at room temperature and 50° C. in solvents such as ethanol (EtOH) and a mixture of methanol (MeOH) and water showed that crystalline form A transformed into crystalline form G, indicating that crystalline form G is more thermodynamically stable.

[0089] In some embodiments, no crystalline form change is observed in the crystalline form G after drying at 50° C. for 3 hours. The crystalline form G also has good solid-state stability, high temperature stability, high humidity stability and pressure stability, as well as low hygroscopicity.

[0090] In another aspect, the present invention also provides a method for preparing the crystalline form G, comprising:

[0091] (1) providing a clear solution of Compound 1 in acetonitrile (ACN) having a first elevated temperature; and

[0092] (2) The solution is allowed to cool naturally to room temperature to obtain the crystalline form G as a solid precipitate.

[0093] In some embodiments, the first elevated temperature is a temperature of about 50-70°C, such as a temperature of about 55-65°C or about 60-65°C, preferably about 60°C.

[0094] In some embodiments, the method comprises stirring the suspension of Compound 1 in acetonitrile at a second elevated temperature and then warming the suspension to the first elevated temperature to obtain the clear solution.

[0095] In some embodiments, the second elevated temperature is a temperature of about 40-60°C, such as a temperature of about 45-55°C or about 50-55°C, preferably about 50°C.

[0096] iii. Form C

[0097] The present invention also provides Form C of Compound I, characterized in that the XRPD spectrum of Form C includes diffraction peaks at the following diffraction angles (2θ): approximately 7.28±0.2°, 10.87±0.2°, 18.39±0.2°, 22.12±0.2° and 23.24±0.2°.

[0098] Alternatively or further, the crystalline form C has any one, two or all of the following characteristics:

[0099] (1) The DSC spectrum of the crystalline form C has a single endothermic peak at approximately 109.0°C ± 3.0°C;

[0100] (2) Form C loses approximately 7.81% of its weight upon heating to approximately 120°C ± 3°C, as measured using TGA;

[0101] (3) the crystal form C 1 The H NMR spectrum is basically as shown in Figure 4-4.

[0102] In some preferred embodiments, the XRPD pattern of the crystalline form C further includes diffraction peaks at any one, multiple or all of the following diffraction angles (2θ): about 11.37±0.2°, 14.67±0.2°, 15.73±0.2°, 18.67±0.2°, 19.39±0.2°, 19.79±0.2°, 20.01±0.2°, 21.66±0.2° and 23.80±0.2°.

[0103] In some preferred embodiments, the XRPD pattern of the crystalline form C further includes diffraction peaks at any one, multiple or all of the following diffraction angles (2θ): about 11.79±0.2°, 17.09±0.2°, 18.96±0.2°, 21.43±0.2°, 22.68±0.2°, 25.01±0.2° and 28.17±0.2°.

[0104] In some preferred embodiments, the DSC spectrum of the crystalline form C is substantially as shown in Figure 4-2.

[0105] In some preferred embodiments, the TGA spectrum of the crystalline form C is substantially as shown in Figure 4-3.

[0106] In some more preferred embodiments, the XRPD pattern of the Form C includes a diffraction peak at a diffraction angle (2θ) substantially the same as that shown in Figure 4-1, and further more preferably, the XRPD pattern of the Form C is as shown in Figure 4-1.

[0107] In some embodiments, the crystalline Form C is a solvate, more specifically a solvate with tetrahydrofuran (THF), wherein preferably, the stoichiometric ratio of the compound I to the THF is about 1:0.72.

[0108] In the DSC test, the Form C was transformed into an amorphous form when heated to 110° C. for 5 minutes.

[0109] In another aspect, the present invention also provides a method for preparing the crystalline form C, comprising:

[0110] (1) providing a clear solution of the compound 1 in THF;

[0111] (2) adding an antisolvent to the clear solution under stirring to obtain the crystalline Form C as a solid precipitate.

[0112] In some embodiments, the antisolvent is water.

[0113] iv. Form D

[0114] The present invention also provides a crystalline form D of compound I, characterized in that the XRPD spectrum of the crystalline form D includes diffraction peaks at the following diffraction angles (2θ): approximately 7.17±0.2°, 10.77±0.2°, 11.36±0.2°, 18.10±0.2°, 19.29±0.2° and 2.95±0.2°.

[0115] Alternatively or further, the crystalline form D has any one, two or all of the following characteristics:

[0116] (1) The DSC spectrum of the crystalline form D has a single endothermic peak with a peak value at approximately 104.1°C ± 3.0°C;

[0117] (2) Form D loses approximately 11.75% weight upon heating to approximately 180°C ± 3°C, as measured using TGA;

[0118] (3) the crystal form D 1 The H NMR spectrum is essentially as shown in Figure 5-4.

[0119] In some preferred embodiments, the XRPD pattern of the crystalline form D further includes diffraction peaks at any one, multiple or all of the following diffraction angles (2θ): about 3.54±0.2°, 11.78±0.2°, 15.62±0.2°, 18.45±0.2° and 21.78±0.2°.

[0120] In some preferred embodiments, the XRPD pattern of the crystalline form D further includes diffraction peaks at any one, multiple or all of the following diffraction angles (2θ): about 14.44±0.2°, 16.93±0.2°, 19.85±0.2°, 22.44±0.2° and 4.39±0.2°.

[0121] In some preferred embodiments, the DSC spectrum of the crystalline form D is substantially as shown in Figure 5-2.

[0122] In some preferred embodiments, the TGA spectrum of the crystalline form D is substantially as shown in Figure 5-3.

[0123] In some more preferred embodiments, the XRPD pattern of the crystalline form D includes a diffraction peak at a diffraction angle (2θ) substantially the same as that shown in Figure 5-1, and further more preferably, the XRPD pattern of the crystalline form D is as shown in Figure 5-1.

[0124] In some embodiments, the crystalline form D is a solvate, more specifically a solvate with 2-methyltetrahydrofuran (2-MeTHF), wherein preferably, the stoichiometric ratio of the compound 1 to the 2-MeTHF is about 1:0.79.

[0125] In the DSC test, the Form D was transformed into an amorphous form when heated to 120° C. for 10 minutes.

[0126] In another aspect, the present invention also provides a method for preparing the crystalline form D, comprising:

[0127] (1) providing a clear solution of the compound 1 in 2-MeTHF;

[0128] (2) adding an antisolvent to the clear solution under stirring to obtain the crystalline form D as a solid precipitate.

[0129] In some embodiments, the antisolvent is heptane (HEP).

[0130] v. Form E

[0131] The present invention also provides a crystalline form E of compound I, characterized in that the XRPD spectrum of the crystalline form E includes diffraction peaks at the following diffraction angles (2θ): approximately 7.29±0.2°, 10.52±0.2°, 11.43±0.2°, 11.87±0.2° and 8.37±0.2°.

[0132] Alternatively or further, the crystalline form E has any one, two or all of the following characteristics:

[0133] (1) The DSC spectrum of the crystalline form E has a single endothermic peak at approximately 105.6°C ± 3.0°C;

[0134] (2) Form E loses approximately 11.46% of its weight upon heating to approximately 140°C ± 3°C, as measured using TGA;

[0135] (3) the crystal form E 1 The H NMR spectrum is essentially as shown in Figure 6-4.

[0136] In some preferred embodiments, the XRPD pattern of the crystalline form E further includes diffraction peaks at any one, multiple or all of the following diffraction angles (2θ): about 13.55±0.2°, 14.67±0.2°, 15.78±0.2°, 17.13±0.2°, 19.28±0.2°, 20.05±0.2°, 21.20±0.2°, 22.08±0.2° and 24.55±0.2°.

[0137] In some preferred embodiments, the DSC spectrum of the crystalline form E is substantially as shown in Figure 6-2.

[0138] In some preferred embodiments, the TGA spectrum of the crystalline form E is substantially as shown in Figure 6-3.

[0139] In some more preferred embodiments, the XRPD pattern of the crystalline form E includes a diffraction peak at a diffraction angle (2θ) substantially the same as that shown in Figure 6-1, and further more preferably, the XRPD pattern of the crystalline form E is as shown in Figure 6-1.

[0140] In some embodiments, the crystalline form E is a solvate, more specifically a solvate with methyl tert-butyl ether (MTBE), wherein preferably, the stoichiometric ratio of the compound I to the MTBE is about 1:0.74.

[0141] In the DSC test, the Form E was transformed into an amorphous form when heated to 120° C. for 10 minutes.

[0142] In another aspect, the present invention also provides a method for preparing the crystalline form E, comprising:

[0143] The amorphous form of Compound I is suspended in MTBE, and the resulting suspension is stirred at a suitable temperature to obtain the crystalline Form E as a solid precipitate.

[0144] In some embodiments, the suitable temperature is, for example, a temperature of about 40-70°C, such as a temperature of about 45-65°C or about 50-60°C, preferably about 50°C.

[0145] In some embodiments, the stirring may be performed for a suitable period of time, such as about 1-2 days.

[0146] vi. Crystal Form Ix

[0147] The present invention also provides a crystalline form Ix of compound I, characterized in that the XRPD spectrum of the crystalline form Ix includes diffraction peaks at the following diffraction angles (2θ): approximately 3.70±0.2°, 7.47±0.2°, 11.24±0.2°, 11.46±0.2°, 15.02±0.2°, 18.82±0.2°, 19.68±0.2°, 22.64±0.2° and 8.24±0.2°.

[0148] Alternatively or further, the crystalline form Ix has any one, two or all of the following characteristics:

[0149] (1) The DSC spectrum of the crystalline form Ix has a single endothermic peak at approximately 113.2°C ± 3.0°C;

[0150] (2) Form Ix loses approximately 8.68% of its weight upon heating to approximately 130°C ± 3°C, as measured using TGA;

[0151] (3) the crystal form Ix 1 The H NMR spectrum is essentially as shown in Figure 7-4.

[0152] In some preferred embodiments, the DSC spectrum of the crystalline form Ix is substantially as shown in Figure 7-2.

[0153] In some preferred embodiments, the TGA pattern of the crystalline form Ix is substantially as shown in Figure 7-3.

[0154] In some more preferred embodiments, the XRPD pattern of the crystalline form Ix includes a diffraction peak at a diffraction angle (2θ) substantially the same as that shown in Figure 7-1, and even more preferably, the XRPD pattern of the crystalline form Ix is as shown in Figure 7-1.

[0155] In some embodiments, the crystalline form Ix is a solvate, more specifically a solvate with acetone, wherein preferably, the stoichiometric ratio of the compound I to the acetone is about 1:0.78.

[0156] In DSC experiments, the crystalline form Ix transformed into an amorphous form when heated to 120° C. for 10 minutes.

[0157] In another aspect, the present invention also provides a method for preparing the crystalline form Ix of Compound I, comprising:

[0158] (1) providing a clear solution of Compound 1 in acetone; and

[0159] (2) allowing the solution to evaporate slowly at room temperature under conditions allowing slow evaporation to obtain the crystalline form Ix as a solid precipitate.

[0160] In some embodiments, the slow volatilization is performed for a suitable period of time, such as about 3 days.

[0161] vii. Crystal Form J

[0162] The present invention also provides Form J of Compound I, characterized in that the XRPD spectrum of Form E includes diffraction peaks at the following diffraction angles (2θ): approximately 7.42±0.2°, 18.10±0.2°, 18.74±0.2°, 19.03±0.2° and 22.13±0.2°.

[0163] Alternatively or further, the crystalline form J has any one, two or all of the following characteristics:

[0164] (1) The DSC spectrum of the crystalline form J has a single endothermic peak at approximately 107.7°C ± 3.0°C;

[0165] (2) Form J loses approximately 10.35% weight upon heating to approximately 130°C ± 3°C, as measured using TGA;

[0166] (3) The crystal form J 1 The H NMR spectrum is essentially as shown in Figure 8-4.

[0167] In some preferred embodiments, the XRPD pattern of the crystalline form J further includes diffraction peaks at any one, multiple or all of the following diffraction angles (2θ): about 3.68±0.2°, 10.58±0.2°, 10.77±0.2°, 11.01±0.2°, 14.95±0.2°, 22.56±0.2°, 24.54±0.2° and 27.27±0.2°.

[0168] In some preferred embodiments, the XRPD pattern of the crystalline form J further includes diffraction peaks at any one, multiple or all of the following diffraction angles (2θ): about 11.67±0.2°, 13.62±0.2°, 16.32±0.2°, 17.59±0.2°, 20.53±0.2°, 25.09±0.2° and 26.05±0.2°.

[0169] In some preferred embodiments, the DSC spectrum of the crystalline form J is substantially as shown in Figure 8-2.

[0170] In some preferred embodiments, the TGA spectrum of the crystalline form J is substantially as shown in Figure 8-3.

[0171] In some more preferred embodiments, the XRPD pattern of the crystalline form J includes a diffraction peak at a diffraction angle (2θ) substantially the same as that shown in Figure 8-1, and further more preferably, the XRPD pattern of the crystalline form J is as shown in Figure 8-1.

[0172] In some embodiments, the crystalline Form J is a solvate, more specifically a solvate with MTBE, wherein preferably, the stoichiometric ratio of the compound I to the MTBE is about 1:0.77.

[0173] In DSC experiments, the Form J transformed into an amorphous form when heated to 120°C for 10 minutes.

[0174] In another aspect, the present invention also provides a method for preparing the crystalline form J, comprising:

[0175] (1) providing a clear solution of Compound 1 in a mixture of EtOH:MTBE (e.g., about 1:3 v:v) having an elevated temperature; and

[0176] (2) The solution is allowed to cool naturally to room temperature to obtain the crystalline form J as a solid precipitate.

[0177] In some embodiments, the elevated temperature is a temperature of about 40-60°C, such as a temperature of about 45-55°C or about 50-55°C, preferably about 50°C.

[0178] In some embodiments, the method comprises stirring a suspension of Compound 1 in the EtOH:MTBE mixture and then warming the suspension to the elevated temperature, thereby dissolving Compound 1 to form the solution.

[0179] viii. Crystal Form K

[0180] The present invention also provides a crystalline form K of compound I, characterized in that the XRPD spectrum of the crystalline form E includes diffraction peaks at the following diffraction angles (2θ): approximately 3.70±0.2°, 7.44±0.2°, 18.74±0.2°, 19.40±0.2° and 22.38±0.2°.

[0181] Alternatively or further, the crystalline form K has any one, two or all of the following characteristics:

[0182] (1) The DSC spectrum of the crystalline form K has a single endothermic peak at approximately 103.8°C ± 3.0°C;

[0183] (2) Form K loses approximately 8.47% of its weight upon heating to approximately 110°C ± 3°C, as measured using TGA;

[0184] (3) The crystal form K 1 The H NMR spectrum is essentially as shown in Figure 9-4.

[0185] In some preferred embodiments, the XRPD pattern of the crystalline form K further includes diffraction peaks at any one, multiple or all of the following diffraction angles (2θ): about 11.20±0.2°, 11.81±0.2°, 14.94±0.2°, 24.73±0.2°, 26.15±0.2° and 27.45±0.2°.

[0186] In some preferred embodiments, the XRPD pattern of the crystalline form K further includes diffraction peaks at any one, multiple or all of the following diffraction angles (2θ): about 13.76±0.2°, 15.82±0.2°, 16.44±0.2°, 17.65±0.2°, 21.14±0.2°, 23.92±0.2° and 25.29±0.2°.

[0187] In some preferred embodiments, the DSC spectrum of the crystalline form K is substantially as shown in Figure 9-2.

[0188] In some preferred embodiments, the TGA spectrum of the crystalline form K is substantially as shown in Figure 9-3.

[0189] In some more preferred embodiments, the XRPD pattern of the crystalline form K includes a diffraction peak at a diffraction angle (2θ) substantially the same as that shown in Figure 9-1, and further more preferably, the XRPD pattern of the crystalline form K is as shown in Figure 9-1.

[0190] In some embodiments, the crystalline form K is a solvate, more specifically a solvate with MTBE, wherein preferably, the stoichiometric ratio of the compound I to the MTBE is about 1:0.47.

[0191] In DSC experiments, the Form K transformed into an amorphous form when heated to 110° C. for 10 minutes.

[0192] In another aspect, the present invention also provides a method for preparing the crystalline form K, comprising:

[0193] (1) providing a clear solution of the compound 1 in a mixture of CH2Cl2:MTBE (e.g., about 1:3 v:v) having an elevated temperature; and

[0194] (2) The solution is allowed to cool naturally to room temperature to obtain the crystalline form K as a solid precipitate.

[0195] In some embodiments, the elevated temperature is a temperature of about 40-60°C, such as a temperature of about 45-55°C or about 50-55°C, preferably about 50°C.

[0196] In some embodiments, the method comprises stirring a suspension of Compound 1 in the mixture of CH2Cl2:MTBE and then warming the suspension to the elevated temperature, thereby dissolving Compound 1 to form the solution.

[0197] ix. Crystal Form L

[0198] The present invention also provides a crystalline form L of compound I, characterized in that the XRPD spectrum of the crystalline form E includes diffraction peaks at the following diffraction angles (2θ): approximately 7.41±0.2°, 11.18±0.2°, 18.72±0.2°, 19.75±0.2° and 22.42±0.2°.

[0199] Alternatively or further, the crystalline form L has any one, two or all of the following characteristics:

[0200] (1) The DSC spectrum of the crystalline form L has a single endothermic peak at approximately 98.1°C ± 3.0°C;

[0201] (2) Form L loses approximately 7.62% weight upon heating to approximately 110°C ± 3°C, as measured using TGA;

[0202] (3) the crystal form L 1 The H NMR spectrum is essentially as shown in Figure 10-4.

[0203] In some preferred embodiments, the XRPD pattern of the crystalline form L further includes diffraction peaks at any one, multiple or all of the following diffraction angles (2θ): about 10.97±0.2°, 11.76±0.2°, 24.73±0.2°, 26.34±0.2° and 27.32±0.2°.

[0204] In some preferred embodiments, the DSC spectrum of the crystalline form L is substantially as shown in Figure 10-2.

[0205] In some preferred embodiments, the TGA spectrum of the crystalline form L is substantially as shown in Figure 10-3.

[0206] In some more preferred embodiments, the XRPD pattern of the crystalline form L includes a diffraction peak at a diffraction angle (2θ) substantially the same as that shown in Figure 10-1, and further more preferably, the XRPD pattern of the crystalline form L is as shown in Figure 10-1.

[0207] In some embodiments, the crystalline form L is a solvate, more specifically a solvate with THF, wherein preferably, the stoichiometric ratio of the compound I to the THF is about 1:0.75.

[0208] In DSC experiments, the Form L transformed into an amorphous form when heated to 120° C. for 10 minutes.

[0209] In another aspect, the present invention also provides a method for preparing the crystalline form L, comprising:

[0210] (1) providing a clear solution of Compound 1 in a mixture of THF:H2O (e.g., about 1:2 v:v) having an elevated temperature; and

[0211] (2) The solution is allowed to cool naturally to room temperature to obtain the crystalline form L as a solid precipitate.

[0212] In some embodiments, the elevated temperature is a temperature of about 40-60°C, such as a temperature of about 45-55°C or about 50-55°C, preferably about 50°C.

[0213] In some embodiments, the method comprises stirring a suspension of Compound 1 in the THF:H 2 O mixture and then warming the suspension to the elevated temperature, thereby dissolving Compound 1 to form the solution.

[0214] x. Crystal Form M

[0215] The present invention also provides a crystalline form M of compound I, characterized in that the XRPD spectrum of the crystalline form E includes diffraction peaks at the following diffraction angles (2θ): approximately 3.51±0.2°, 7.11±0.2°, 14.28±0.2°, 17.93±0.2°, 21.58±0.2° and 25.25±0.2°.

[0216] Alternatively or further, the crystalline form M has any one, two or all of the following characteristics:

[0217] (1) The DSC spectrum of the crystalline form M has two endothermic peaks at approximately 95.8°C ± 3.0°C and approximately 109.2°C ± 3.0°C, respectively;

[0218] (2) the Form M loses approximately 15.55% weight during heating to approximately 230°C ± 3°C, as measured using TGA;

[0219] (3) the crystal form M 1 The H NMR spectrum is essentially as shown in Figure 11-4.

[0220] In some preferred embodiments, the DSC spectrum of the crystalline form M is substantially as shown in Figure 11-2.

[0221] In some preferred embodiments, the TGA spectrum of the crystalline form M is substantially as shown in Figure 11-3.

[0222] In some more preferred embodiments, the XRPD pattern of the crystalline form M includes a diffraction peak at a diffraction angle (2θ) substantially the same as that shown in Figure 11-1, and further more preferably, the XRPD pattern of the crystalline form M is as shown in Figure 11-1.

[0223] In some embodiments, the crystalline form M is a solvate, more specifically a solvate with anisole, wherein preferably, the stoichiometric ratio of the compound I to the anisole is about 1:1.

[0224] In DSC experiments, the Form M transformed into an amorphous form when heated to 105°C for 10 minutes.

[0225] In another aspect, the present invention also provides a method for preparing the crystalline form M, comprising:

[0226] (1) providing a clear solution of Compound 1 in a mixture of anisole:HEP (e.g., about 9:1 v:v) having an elevated temperature; and

[0227] (2) allowing the solution to cool naturally to room temperature to obtain the crystalline form M as a solid precipitate.

[0228] In some embodiments, the elevated temperature is a temperature of about 40-60°C, such as a temperature of about 45-55°C or about 50-55°C, preferably about 50°C.

[0229] In some embodiments, the method comprises stirring a suspension of Compound 1 in the anisole:HEP mixture and then warming the suspension to the elevated temperature, thereby dissolving Compound 1 to form the solution.

[0230] xi. Crystal Form N

[0231] The present invention also provides a crystalline form N of compound I, characterized in that the XRPD spectrum of the crystalline form N includes diffraction peaks at the following diffraction angles (2θ): approximately 3.57±0.2°, 7.23±0.2°, 14.57±0.2°, 18.26±0.2° and 21.96±0.2°.

[0232] Alternatively or further, the crystalline form N has any one, two or all of the following characteristics:

[0233] (1) The DSC spectrum of the crystalline form N has a single endothermic peak at approximately 106.8°C ± 3.0°C;

[0234] (2) Form N loses approximately 11.80% weight during heating to approximately 180°C ± 3°C, as measured using TGA;

[0235] (3) the crystal form N 1 The H NMR spectrum is essentially as shown in Figure 12-4.

[0236] In some preferred embodiments, the XRPD pattern of the crystalline form N further includes diffraction peaks at any one, multiple or all of the following diffraction angles (2θ): about 10.91±0.2°, 22.95±0.2°, 23.88±0.2° and 37.08±0.2°.

[0237] In some preferred embodiments, the DSC spectrum of the crystalline form N is substantially as shown in Figure 12-2.

[0238] In some preferred embodiments, the TGA spectrum of the crystalline form N is substantially as shown in Figure 12-3.

[0239] In some more preferred embodiments, the XRPD pattern of the crystalline form N includes a diffraction peak at a diffraction angle (2θ) substantially the same as that shown in Figure 12-1, and further more preferably, the XRPD pattern of the crystalline form N is as shown in Figure 12-1.

[0240] In some embodiments, the crystalline form N is a solvate, more specifically a solvate with isopropyl alcohol (IPA), wherein preferably, the stoichiometric ratio of the compound I to the IPA is about 1:0.82.

[0241] In DSC experiments, the Form N transformed into an amorphous form when heated to 120° C. for 10 minutes.

[0242] In another aspect, the present invention also provides a method for preparing the crystalline form N of Compound I, comprising:

[0243] (1) providing a solution of Compound 1 in a mixture of IPA:H2O (e.g., about 4:1 v:v); and

[0244] (2) allowing the solution to evaporate slowly at room temperature under conditions allowing slow evaporation to obtain the crystalline form N as a solid precipitate.

[0245] In some embodiments, the slow volatilization is performed for a suitable period of time, such as about 6-10 days or about 8-9 days.

[0246] xii. Crystalline Form O

[0247] The present invention also provides a crystalline form O of compound I, characterized in that the XRPD spectrum of the crystalline form O includes diffraction peaks at the following diffraction angles (2θ): approximately 7.54±0.2°, 10.95±0.2°, 18.88±0.2°, 19.79±0.2° and 22.62±0.2°.

[0248] Alternatively or further, the crystalline form O has any one, two or all of the following characteristics:

[0249] (1) The DSC spectrum of the crystalline form O has a single endothermic peak at approximately 95.5°C ± 3.0°C;

[0250] (2) Form O loses approximately 5.38% of its weight upon heating to approximately 110°C ± 3°C, as measured using TGA;

[0251] (3) The crystal form O 1 The H NMR spectrum is essentially as shown in Figure 13-4.

[0252] In some preferred embodiments, the XRPD pattern of the crystalline form O further includes diffraction peaks at any one, multiple or all of the following diffraction angles (2θ): about 11.44±0.2°, 11.88±0.2°, 13.75±0.2° and 21.19±0.2°.

[0253] In some preferred embodiments, the XRPD pattern of the crystalline form O further includes diffraction peaks at any one, multiple or all of the following diffraction angles (2θ): about 15.05±0.2°, 15.87±0.2°, 16.17±0.2°, 24.95±0.2°, 26.44±0.2° and 27.66±0.2°.

[0254] In some preferred embodiments, the XRPD pattern of the crystalline form O further includes diffraction peaks at any one, multiple or all of the following diffraction angles (2θ): about 17.45±0.2°, 21.86±0.2°, 23.85±0.2° and 25.72±0.2°.

[0255] In some preferred embodiments, the DSC spectrum of the crystalline form O is substantially as shown in Figure 13-2.

[0256] In some preferred embodiments, the TGA spectrum of the crystalline form O is substantially as shown in Figure 13-3.

[0257] In some more preferred embodiments, the XRPD pattern of the crystalline form O includes a diffraction peak at a diffraction angle (2θ) substantially the same as that shown in Figure 13-1, and further more preferably, the XRPD pattern of the crystalline form O is as shown in Figure 13-1.

[0258] In some embodiments, the crystalline form O is a solvate, more specifically a solvate with acetone, wherein preferably, the stoichiometric ratio of the compound I to the acetone is about 1:0.5.

[0259] In DSC experiments, the Form O transformed into an amorphous form when heated to 120° C. for 10 minutes.

[0260] In another aspect, the present invention also provides a method for preparing the crystalline form O of Compound I, comprising:

[0261] The amorphous form of Compound 1 is contacted with acetone vapor in a sealed container for a suitable period of time to obtain the Form O.

[0262] In some embodiments, the suitable period of time can be, for example, about 9-10 days.

[0263] xiii. Other crystal forms

[0264] The present invention also provides a metastable crystalline form of Compound I, including:

[0265] (1) Form B, whose XRPD pattern is substantially as shown in FIG14 , which converts to an amorphous form after drying at about 50° C. for 3 hours;

[0266] (2) Form H, whose XRPD pattern is substantially as shown in FIG15 , becomes weakly crystalline after drying at about 50° C. for 2 hours;

[0267] (3) Form F, whose XRPD pattern is substantially as shown in FIG16 , transforms into Form D after being sealed and placed at room temperature for 21 days;

[0268] (4) Form P, whose XRPD pattern is substantially as shown in FIG17 , converts to an amorphous form after drying at about 50° C. for 3.5 hours.

[0269] II. Pharmaceutical Compositions

[0270] In another aspect, the present invention provides a pharmaceutical composition comprising a crystalline form of Compound I according to the present invention, wherein the crystalline form of Compound I is selected from the above-described Form A, Form B, Form C, Form D, Form E, Form F, Form G, Form H, Form Ix, Form J, Form K, Form L, Form M, Form N, Form O, and Form P. Preferably, the crystalline form of Compound I is selected from Form A, Form C, Form D, Form E, Form G, Form Ix, Form J, Form K, Form L, Form M, Form N, and Form O. More preferably, the crystalline form of Compound I is Form A or Form G, even more preferably Form G.

[0271] The present invention also provides a pharmaceutical composition as described above, which further comprises one, two or more other therapeutically active ingredients.

[0272] The pharmaceutical composition of the present invention may further comprise a pharmaceutically acceptable carrier.

[0273] In the present invention, "pharmaceutically acceptable carrier" refers to a diluent, adjuvant, excipient or vehicle that is administered together with the therapeutic agent and is suitable for contact with the tissues of humans and / or other animals without excessive toxicity, irritation, allergic response or other problems or complications corresponding to a reasonable benefit / risk ratio within the scope of reasonable medical judgment.

[0274] Pharmaceutically acceptable carriers that can be used in the pharmaceutical compositions of the present invention include, but are not limited to, sterile liquids, such as water and oils, including those of petroleum, animal, plant, or synthetic origin, such as peanut oil, soybean oil, mineral oil, sesame oil, and the like. When the pharmaceutical composition is administered intravenously, water is an exemplary carrier. Physiological saline and aqueous glucose and glycerol solutions can also be used as liquid carriers, particularly for injections. Suitable pharmaceutical excipients include starch, glucose, lactose, sucrose, gelatin, maltose, chalk, silica gel, sodium stearate, glycerol monostearate, talc, sodium chloride, skim milk powder, glycerol, propylene glycol, water, ethanol, and the like. The composition may also contain a small amount of a wetting agent, emulsifier, or pH buffer, as needed. Oral formulations may contain standard carriers, such as pharmaceutical grade mannitol, lactose, starch, magnesium stearate, sodium saccharin, cellulose, magnesium carbonate, and the like. Examples of suitable pharmaceutically acceptable carriers are described in Remington's Pharmaceutical Sciences (1990).

[0275] The pharmaceutical compositions of the present invention can act systemically and / or locally. For this purpose, they can be administered by suitable routes, for example, by injection, intravenous, intraarterial, subcutaneous, intraperitoneal, intramuscular or transdermal administration; or by oral, buccal, nasal, transmucosal, topical, in the form of ophthalmic preparations or by inhalation.

[0276] For these administration routes, the pharmaceutical composition of the present invention can be administered in suitable dosage forms.

[0277] The dosage forms include, but are not limited to, liquid preparations, semisolid preparations, and solid preparations. Solid or semisolid preparations include, but are not limited to, capsules, tablets, pills, lozenges, dragees, granules, powders, ointments, and creams. Liquid preparations include, but are not limited to, elixirs, syrups, emulsions, dispersions, suspensions, solutions, sprays, and drops.

[0278] As used herein, the term "therapeutically effective amount" refers to that amount of a compound which, when administered, will relieve to some extent one or more of the symptoms of the disease or condition being treated.

[0279] The dosage regimen can be adjusted to provide the optimal desired response. For example, a single bolus can be administered, several divided doses can be administered over time, or the dose can be proportionally reduced or increased as indicated by the urgency of the therapeutic situation. It is to be noted that dosage values ​​can vary with the type and severity of the condition to be alleviated and can include single or multiple doses. It is to be further understood that for any particular individual, the specific dosage regimen should be adjusted over time according to the individual's needs and the professional judgment of the person administering or supervising the administration of the composition.

[0280] The amount of the compound of the present invention administered will depend on the severity of the individual, disease or the patient's condition, the speed of administration, the disposal of the compound and the judgment of the prescribing physician for treatment. Generally speaking, effective dose is about 0.0001 to about 50mg per kg body weight per day, for example, about 0.01 to about 10mg / kg / day (single or divided administration). For 70kg people, this will add up to about 0.007mg / day to about 3500mg / day, for example, about 0.7mg / day to about 700mg / day. In some cases, it can be enough to be not higher than the dosage level of the lower limit of the aforementioned range, and in other cases, it is still possible to adopt a larger dose in the case of not causing any harmful side effects, provided that the larger dose is first divided into several smaller doses to be administered throughout the day.

[0281] The compound of the present invention may be present in the pharmaceutical composition in an amount ranging from about 0.01 mg to about 1000 mg.

[0282] As used herein, the term "treating" means reversing, alleviating, inhibiting the progression of the disease or condition to which such term applies, or one or more symptoms of such a disease or condition. As used herein, the term "preventing" means preventing or arresting the development of the disease or condition to which such term applies, or the appearance of one or more symptoms of such a disease or condition.

[0283] As used herein, "subject" includes humans and non-human animals. Exemplary human subjects include human subjects suffering from diseases (e.g., the diseases described herein) (referred to as patients) or normal individuals. "Non-human animals" herein include all vertebrates, such as non-mammals (e.g., birds, amphibians, reptiles) and mammals, such as non-human primates, livestock and / or domesticated animals (e.g., sheep, dogs, cats, cows, pigs, etc.).

[0284] III. Uses and Treatment Methods

[0285] The crystalline form of Compound I of the present invention has excellent GLP-1 receptor agonist activity and can treat and / or prevent GLP-1 receptor-mediated diseases and related disorders.

[0286] Therefore, in one aspect, the present invention provides a method for treating and / or preventing GLP-1 receptor-mediated diseases or related conditions, comprising administering to a subject in need thereof an effective amount of a crystalline form of Compound I or a pharmaceutical composition of the present invention.

[0287] In another aspect, the present invention provides a crystalline form of Compound I according to the present invention or a pharmaceutical composition according to the present invention for use in the treatment and / or prevention of GLP-1 receptor mediated diseases and related conditions.

[0288] In another aspect, the present invention provides use of the crystalline form of Compound I of the present invention or the pharmaceutical composition of the present invention in the preparation of a medicament for treating and / or preventing a GLP-1 receptor-mediated disease or related condition.

[0289] In another aspect, the present invention provides a method for treating and / or preventing metabolic-related diseases or disorders, comprising administering to a subject in need thereof an effective amount of the crystalline form of Compound I of the present invention or the pharmaceutical composition of the present invention.

[0290] In another aspect, the present invention provides a crystalline form of Compound I according to the invention or a pharmaceutical composition according to the invention for use in the treatment and / or prevention of a metabolic-related disease or disorder.

[0291] In another aspect, the present invention provides use of the crystalline form of Compound I of the present invention or the pharmaceutical composition of the present invention in the preparation of a medicament for treating and / or preventing a metabolic-related disease or disorder.

[0292] In some embodiments, the metabolic-related diseases or disorders include GLP-1 receptor-mediated diseases and related disorders.

[0293] In some embodiments, the GLP-1 receptor mediated disease or related condition is selected from the group consisting of diabetes, hyperglycemia, insulin resistance, glucose intolerance, diabetic nephropathy, diabetic neuropathy, diabetic retinopathy, adipocyte dysfunction, obesity, nonalcoholic fatty liver disease, dyslipidemia, and hyperinsulinemia.

[0294] In some embodiments, the diabetes is selected from the group consisting of: T1D and / or T2DM, idiopathic T1D, early-onset T2DM, latent autoimmune diabetes, atypical diabetes of the juvenile, and gestational diabetes.

[0295] In some embodiments, the GLP-1 receptor mediated disease or related condition is obesity.

[0296] In some embodiments, the GLP-1 receptor mediated disease or related condition is T2DM.

[0297] In some embodiments, the GLP-1 receptor mediated disease or related condition is non-alcoholic fatty liver disease.

[0298] In some embodiments, the crystalline form of Compound 1 is selected from the above-described Form A, Form B, Form C, Form D, Form E, Form F, Form G, Form H, Form Ix, Form J, Form K, Form L, Form M, Form N, Form O, and Form P. Preferably, the crystalline form of Compound 1 is selected from Form A, Form C, Form D, Form E, Form G, Form Ix, Form J, Form K, Form L, Form M, Form N, and Form O. More preferably, the crystalline form of Compound 1 is Form A or Form G, even more preferably Form G. Beneficial effects

[0299] The crystalline forms of Compound I of the present invention, preferably Form A and Form G, have favorable physicochemical properties, such as low hygroscopicity and favorable physicochemical stability (solid-state stability, high temperature resistance, high humidity resistance, and / or high pressure resistance). Form G has higher thermodynamic stability at temperatures between room temperature and 50°C. Form G also has higher pressure stability. The crystalline forms of Compound I have the potential to have favorable drugability and / or bioavailability.

[0300] Example

[0301] The present invention will be further described below by way of examples. The examples of the present invention are intended only to illustrate the technical solutions of the present invention and are not intended to limit the scope of the present invention. Those skilled in the art may make some non-essential improvements and adjustments, which still fall within the scope of protection of the present invention.

[0302] All solvents used in the examples were commercially available and used without further purification.

[0303] The abbreviations used in this application have the following meanings: rt represents room temperature; H2O represents water; CH2Cl2 represents dichloromethane; THF represents tetrahydrofuran; IPA represents isopropyl alcohol; 2-MeTHF represents 2-methyltetrahydrofuran; NMP represents N-methylpyrrolidone; DME represents ethylene glycol dimethyl ether; DCM represents dichloromethane; Xphos represents 2-dicyclohexylphosphino-2'4'6'-triisopropylbiphenyl; EtOAc represents ethyl acetate; MeOH represents methanol; 2-Me-THF represents 2-methyltetrahydrofuran; DAS represents 1,2-dihydro-2,4'6'-triisopropylbiphenyl; T represents diethylaminosulfur trifluoride; TFE represents tetrafluoroethylene; ACN represents acetonitrile; CPME represents cyclopentyl methyl ether; DMSO represents dimethyl sulfoxide; EtOH represents ethanol; TFA represents trifluoroacetic acid; TsOH represents p-toluenesulfonic acid; MIBK represents methyl isobutyl ketone; HEP represents n-heptane; IPAc represents isopropyl acetate; EtOAc represents ethyl acetate; DMF represents N,N-dimethylformamide; MTBE represents methyl tert-butyl ether; MEK represents methyl ethyl ketone; CHCl3 represents chloroform; and MCH represents methylcyclohexane.

[0304] Compounds are manually or Software naming, commercially available compounds use supplier catalog names.

[0305] The instruments and parameters used in this application are as follows:

[0306] 1. X-ray powder diffractometer (XRPD)

[0307] Table 1: XRPD test parameters

[0308] 2. Thermogravimetric Analysis (TGA) and Differential Scanning Calorimeter (DSC)

[0309] Table 2: TGA and DSC test parameters

[0310] 3. High Performance Liquid Chromatography (HPLC)

[0311] Table 3: HPLC test parameters

[0312] 4. Dynamic Vapor Sorption (DVS) Determination

[0313] Table 4: DVS test parameters

[0314] 5. H NMR spectroscopy ( 1 H NMR)

[0315] Table 5: 1 H NMR test parameters

[0316] Example 1: Preparation of Compound I

[0317] Synthesis route:

[0318] Preparation method:

[0319] Compound 1-2: To a solution of 1-1 (20.0 g, 98.0 mmol) in MeCN (500 mL) was added imidazole (10.0 g, 147.0 mmol), followed by TBSCl (16.3 g, 107.8 mmol). The mixture was stirred at room temperature for 5 hours. H2O (500 mL) was added, and the reaction solution was extracted with EtOAc (3×500 mL). The combined organic phases were washed with brine (500 mL), dried (Na2SO4), filtered, and concentrated. Flash chromatography (SiO2, hexane) afforded 31 g of compound 1-2. Yield: 99.6%. 1 H NMR (400MHz, DMSO-d6) δ7.35(m,3H),4.62(s,2H),0.81(s,9H),0.00(s,6H).

[0320] Compound 1-3: To a solution of 1-2 (20.0 g, 62.8 mmol) in anhydrous THF (200 mL) was added dropwise N-BuLi (2.5 M in THF, 27.6 mL, 69.1 mmol) under N2 at -78°C. The mixture was stirred at this temperature for 0.5 hours, and then oxetane-3-one (4.5 g, 62.8 mmol) was added. The mixture was then stirred at room temperature for 2.5 hours under N2 atmosphere. The reaction solution was quenched with water (100 mL) and extracted with EtOAc (3×100 mL). The combined organic phases were washed with brine (100 mL), dried (Na2SO4), filtered and concentrated. Flash chromatography (SiO2, 25% EtOAc-hexane) gave 14 g of compound 1-3. Yield: 71.0%. 1 H NMR (400MHz, DMSO-d6) δ7.42–7.33(m,2H),7.26–7.18(m,1H),6.36(s,1H),4.69–4.53(m,6H),0.81(s,9H),-0.00(s,6H).

[0321] Compound 1-4: To a solution of 1-3 (14.0 g, 44.8 mmol) in anhydrous THF (200 mL) was added NaH (3.6 g, 89.7 mmol) at 0°C and the mixture was stirred at room temperature for 2 hours. CS2 (3.6 g, 44.8 mmol) and MeI (6.4 g, 44.8 mmol) were then added at 0°C under N2. The mixture was then stirred at 0°C under N2 for 0.5 hours. The reaction solution was quenched with saturated NH4Cl solution (100 mL) and extracted with EtOAc (3×200 mL). The combined organic phases were washed with brine (200 mL), dried (Na2SO4), filtered and concentrated to give 14 g of compound 1-4. The product was used directly in the next step without further purification.

[0322] Compound 1-5: To a solution of 1-4 (14.0 g, 44.8 mmol) in toluene (200 mL) was added (n-Bu)3SnH (26.2 g, 89.7 mmol), followed by AIBN (736 mg, 4.4 mmol). Under an N2 atmosphere, the mixture was stirred at 125°C for 0.5 h. The reaction solution was concentrated and purified by flash chromatography (SiO2, 20% EtOAc-hexane) to afford 8 g of compound 1-5. Two-step yield: 60.6%. 1 H NMR(400MHz, DMSO-d6)δ7.41(t,J=8.0Hz,1H),7.23–7.16(m,2H),4.91(dd,J=8.3,5.9H z,2H),4.72(s,2H),4.59(t,J=6.3Hz,2H),4.30–4.18(m,1H),0.88(s,9H),0.07(s,6H).

[0323] Compound 1-6: To a solution of 1-5 (8.0 g, 43.0 mmol) in THF (200 mL) was added Et3N·HF3 (13.9 g, 86.0 mmol). The reaction solution was stirred at room temperature under a N2 atmosphere for 16 hours. The reaction solution was concentrated and purified by flash chromatography (SiO2, EtOAc-hexane) to afford 5 g of compound 1-6. Yield: 99.9%. 1 H NMR (400MHz, DMSO-d6) δ7.44(t,J=7.8Hz,1H),7.20(t,J=9.1Hz,2H),5.22(t,J=5.7Hz,1H), 4.92(dd,J=8.0,6.1Hz,2H), 4.59(t,J=6.3Hz,2H), 4.52(d,J=5.6Hz,2H), 4.30–4.18(m,1H).

[0324] Compound 1-7: To a solution of 1-6 (4.8 g, 26.3 mmol) in DCM (100 mL) was added NBS (5.2 g, 29.0 mmol), followed by the addition of PPh (7.7 g, 29.0 mmol) at 0°C. The mixture was stirred at room temperature under an N atmosphere for 5 hours. H2O (100 mL) was added, and the reaction solution was extracted with DCM (3×100 mL). The combined organic phases were washed with brine (100 mL), dried (Na2SO4), filtered, and concentrated. Purification by flash chromatography (SiO2, EtOAc-hexane) afforded 2 g of compound 1-7. Yield: 30.7%. 1H NMR (400MHz, DMSO-d6) δ7.53(t,J=8.0Hz,1H),7.33–7.20(m,2H),4.92(dd,J=8.3,6.0Hz,2H),4.70(s,2H),4.60(t,J=6.3Hz,2H),4.34–4.20(m,1H).

[0325] Compound 1-8: Mixture 1-7 (600 mg, 2.45 mmol) and tert-butyl 4-(6-hydroxypyridin-2-yl)piperidine-1-carboxylate (684 mg, 2.45 mmol) were added to a solvent DMF (50 mL). Cs2CO3 (2.4 g, 7.37 mmol) was then added. The reaction solution was stirred at room temperature for 16 hours. H2O (50 mL) was added and the reaction solution was extracted with EtOAc (3×50 mL). The combined organic phases were washed with brine (50 mL), dried (Na2SO4), filtered and concentrated. Flash chromatography (SiO2, EtOAc-hexane) was used to purify 500 mg of compound 1-8. Yield: 45.9%. 1 H NMR (400MHz, CDCl3) δ7.60(t,J=7.7Hz,1H),7.46(t,J=7.6Hz,1H),7.17(s,1 H),7.13(d,J=11.4Hz,1H),6.75(d,J=7.3Hz,1H),6.68(d,J=8.1Hz,1H),5.4 3(d,J=7.5Hz,3H),5.33(s,1H),4.45(s,2H),4.14(d,J=14.0Hz,2H),3.03(t ,J=12.8Hz,1H),2.80(t,J=12.9Hz,2H),1.85(d,J=12.5Hz,2H),1.57-1.61(m 3H),1.42(s,9H). / LC-MS(ESI)m / z:443.2[M + H] + .

[0326] Compound 1-9: TFA (10 mL) was added to a DCM (10 mL) solution of 1-8 (210 mg, 0.49 mmol). The reaction solution was stirred at room temperature for 3 hours and concentrated to obtain 250 mg of compound 1-9. LC-MS: MC20-1128-086C (ESI) m / z: 343.1 [M + H] + .

[0327] Compound 1-10: Mixture 1-9 (200 mg, 0.58 mmol) and (S)-2-(chloromethyl)-1-(oxetane-2-ylmethyl)-1H-benzo[d]imidazole-6-carboxylic acid methyl ester (172 mg, 0.58 mmol) were added to a solvent of dioxane (20 mL) and MeCN (12 mL), followed by the addition of K2CO3 (162 mg, 1.16 mmol). The reaction solution was stirred at 65°C for 3 hours. H2O (20 mL) was added, and the reaction solution was extracted with EtOAc (3×20 mL). The combined organic phases were washed with brine (20 mL), dried (Na2SO4), filtered, and concentrated. Flash chromatography (SiO2, EtOAc-hexane) gave 60 mg of compound 1-10. Yield: 22.0%. 1 H NMR (400MHz, DMSO-d6) δ8.30 (d, J=1.1Hz, 1H), 7.82 (dd, J=8.5, 1.6Hz, 1H), 7. 70–7.59(m,2H),7.53(t,J=7.8Hz,1H),7.27(d,J=11.3Hz,1H),7.21(d,J=9.5 Hz,1H),6.86(d,J=7.4Hz,1H),6.65(d,J=8.0Hz,1H),5.38(s,2H),5.35–5.30 (m,1H),5.12(qd,J=7.0,2.5Hz,1H),4.90(dd,J=8.3,6.0Hz,2H),4.80-4.84(m 1H),4.65-4.71(m,1H),4.58(t,J=6.4Hz,2H),4.47(dt,J=8.3,6.5Hz,1H),4.37(dt,J=9.1,5.9Hz,1H),4.21-4.28 (m,1H),3.94-4.02(m,1H),3.87(s,3H),3.78(d,J=13.6Hz,1H),3.01(d,J=9.4Hz,1H),2.85(d,J=13.5Hz,1H ),2.73–2.59(m,2H),2.27(d,J=10.0Hz,1H),2.17(d,J=11.6Hz,1H),1.76(m,4H). / LC-MS(ESI)m / z:601.4[M + H] + .

[0328] Compound 1: To a solution of 1-10 (60 mg, 0.1 mmol) in MeOH (1 mL) and THF (5 mL) was added 1 M LiOH (2 mL). The reaction solution was stirred at room temperature for 3 hours, concentrated, and purified by preparative HPLC to give 10.95 mg of a white solid, Compound 1. Yield: 18.6%. 1 H NMR (400MHz, DMSO-d6) δ8.20(s,1H),7.79(dd,J1=4.0Hz,,J2=8.0Hz,1H),7.62(t,J=8.0Hz,1H),7.54(t,J=8.0Hz,1H),7.45(d,J=8.0Hz,1H),7. 27(d,J=12.0Hz,1H),7.21(d,J=8.0Hz,1H),6.87(d,J=8.0Hz,1H),6.65( d,J=8.0Hz,1H),5.38(s,2H),5.12(m,1H),4.90(dd,J=8.0Hz,2H),4.77( dd,J1=4.0Hz,J2=16.0Hz,1H),4.64(d,J=4.0Hz,1H),4.58(m,2H),4.50– 4.44(m,1H),4.38(m,1H),4.29–4.19(m,1H),3.94(d,J=12.0Hz,1H),3.7 7(d,J=12.0Hz,1H),3.00(d,J=12.0Hz,1H),2.86(d,J=12.0Hz,1H),2.71 (m,1H),2.64–2.56(m,1H),2.47–2.42(m,1H),2.21(m,2H),1.73(m,4H).

[0329] XRPD analysis showed that Compound I was in an amorphous form. Its XRPD pattern is shown in FIG1 .

[0330] Example 2. GLP-1R agonist activity assay of compound I

[0331] (1) Testing instruments and reagents

[0332] Table 6: Bioactivity test instruments and reagents

[0333] (2) GLP-1R test kit

[0334] GLP-1R mediated agonist activity is determined by a cell-based functional assay using a homogeneous time-resolved fluorescence (HTRF) cAMP detection kit that measures cAMP levels in cells. This method is a competitive immunoassay. It enables direct pharmacological characterization of compounds that act on Gs-coupled receptors in adherent or suspension cells.

[0335] Native cAMP produced by cells or unlabeled cAMP standard curve competes with D2-labeled cAMP red receptor for binding to a monoclonal anti-cAMP cryptate europium donor. The specific signal is inversely proportional to the concentration of cAMP in the standard or experimental sample.

[0336] The human GLP-1R coding sequence (NCBI reference sequence NP_002053.3) was subcloned into pEGFP-N1 (tsingke), and cell lines stably expressing the receptor were isolated. The GLP-1R expression density was confirmed by observing GFP expression under a fluorescence microscope.

[0337] (3) GLP-1R-GFP-293A cell culture

[0338] 293A GFP-GLP-1R cells were cultured in DMEM growth medium, 10% heat-inactivated fetal bovine serum (GEMINI Cat#900-108), 1% Pen-3Trep (Sangom Biotech Cat#E607011-0100) and incubated at 37°C in a humidified 5% CO2 incubator.

[0339] (4) cAMP level test method

[0340] The test compound (in DMSO) at various concentrations was diluted 1:5 in distilled water in stimulation buffer, 500 μM 3-isobutyl-1-methylxanthin (IBMX; Meilunbiocat# MB5226) was added to obtain a 2X compound working solution, and then 5 μL of the compound was added to a white 384-well assay plate (Corning 3824) using a multichannel pipette. The final DMSO concentration in the assay buffer mixture was 1‰.

[0341] Cells were harvested from a T25 tissue culture flask and centrifuged at 1000 rpm for 5 minutes at room temperature. The cell pellet was then resuspended in 1 mL of stimulation buffer. A 20 μL sample of the cell suspension was counted on a STAR IC1000 counter to determine cell viability and cell count per mL. The remaining cell suspension was then adjusted with stimulation buffer to deliver 2000 viable cells per well using a multichannel pipette. 5 μL of the cell suspension was added to each well of the assay plate containing the compound. The plate was sealed and incubated at 37°C with 5% CO2 for 30 minutes.

[0342] After a 30-minute incubation, 5 μL of d2-labeled cAMP and 5 μL of anti-cAMP cryptate (both diluted 1:20 in cell lysis buffer) were added to each well of the assay plate. The plates were then incubated at room temperature, and after 60 minutes, the HTRF signal was read using a Tecan Spark plate reader, with excitation at 340 nm and emission at 615 nm and 665 nm. Raw data were converted to nM cAMP by interpolation from a cAMP standard curve, and the percent effect was determined relative to the saturating concentration of the full agonist GLP-17-37 (400 nM) included on each plate. EC 50 Assays were made from agonist dose-response curves analyzed with a curve fitting program using a 4-parameter logistic dose-response equation.

[0343] This study demonstrates that Compound I activates GLP-1R signaling through the cAMP pathway and thus acts as a GLP-1R agonist. The experimental data are presented as geometric means (EC 50 s) to present the results.

[0344] Experimental results: Compound I has a strong agonistic effect on GLP-1R.

[0345] Example 3: Preparation of a crystalline form of Compound I

[0346] Using the amorphous form as the starting material, a total of 16 polymorphic forms were screened out in 111 polymorph screening tests, including slow volatilization, 4-8°C slurry, room temperature slurry, 50°C slurry, anti-solvent addition, anti-antisolvent addition, cooling crystallization, gas-liquid diffusion, gas-solid diffusion, water vapor stress, polymer induction, grinding, cyclic heating and cooling, and rotary evaporation. Among them, the 12 crystal forms described in Example 3 were all stable crystal forms, including crystal forms A and G which were anhydrate crystal forms, and the rest were corresponding solvate crystal forms.

[0347] 1. Crystalline Form A

[0348] 200.49 mg of amorphous compound I was suspended in 5 mL of a mixture of acetone / H2O (1 / 4, v / v). After the suspension was magnetically stirred at 50°C for about 1 day, the solid was separated to obtain Form A, whose XRPD pattern is shown in Figure 2-1.

[0349] 2. Crystal Form G

[0350] 199.87 mg of amorphous Compound I was suspended in 18 mL of ACN. The suspension was stirred at 50°C, then heated to 60°C to dissolve. The suspension was then filtered and the clear solution was allowed to cool naturally to room temperature. The solid was separated to obtain Form G, whose XRPD pattern is shown in Figure 3-1.

[0351] 3. Crystalline Form C

[0352] 19.94 mg of Compound I was dissolved in 0.5 mL of THF and filtered. 1.0 mL of H2O was then added to the clear solution under magnetic stirring. A large amount of white precipitate was precipitated. The isolated solid was Form C, whose XRPD pattern is shown in Figure 4-1.

[0353] 4. Crystal Form D

[0354] 19.81 mg of Compound I was dissolved in 0.5 mL of 2-MeTHF and filtered. Then, 1.0 mL of HEP was added to the clear solution under magnetic stirring. A large amount of precipitate was separated and the solid was Form D. Its XRPD pattern is shown in Figure 5-1.

[0355] 5. Crystal Form E

[0356] 100.18 mg of amorphous compound I was added to a 20 mL vial, followed by 2.5 mL of MTBE. The resulting suspension was magnetically stirred at 50°C for approximately 1 day, and then the solid was collected by centrifugation to obtain Form E, whose XRPD pattern is shown in Figure 6-1.

[0357] 6. Crystal Form Ix

[0358] 99.79 mg of amorphous Compound 1 was added to 4.0 mL of acetone and filtered. The filtrate was sealed in a vial with parafilm, which was then punctured and allowed to evaporate slowly at room temperature for 3 days. The resulting solid was collected, representing Form Ix. Its XRPD pattern is shown in Figure 7-1.

[0359] 7. Crystal Form J

[0360] 20.05 mg of Compound I was suspended in 0.8 mL of a mixture of EtOH / MTBE (1 / 3 v / v). The suspension was clarified at 50°C and then filtered. The clarified solution was allowed to cool to room temperature, and a solid was isolated, which was Form J. Its XRPD pattern is shown in Figure 8-1.

[0361] 8. Crystal Form K

[0362] 20 mg of Compound I was suspended in 1.2 mL of a mixture of CH2Cl2 / MTBE (1 / 3 v / v). The suspension was clarified at 50°C and then filtered. The clarified solution was allowed to cool naturally to room temperature, and a solid was isolated, which was Form K. Its XRPD pattern is shown in Figure 9-1.

[0363] 9. Crystal Form L

[0364] 100.14 mg of Compound I was suspended in 9.0 mL of a 1 / 2 v / v mixture of THF and H2O. The suspension was clarified at 50°C and then filtered. The clarified solution was allowed to cool to room temperature, and a solid was isolated, which was Form L. Its XRPD pattern is shown in Figure 10-1.

[0365] 10. Crystal Form M

[0366] 99.83 mg of Compound I was suspended in 10 mL of a mixture of anisole and HEP (9 / 1 v / v). The suspension was clarified at 50°C and then filtered. The clarified solution was allowed to cool to room temperature, and a solid was isolated, which was Form M. Its XRPD pattern is shown in Figure 11-1.

[0367] 11. Crystal Form N

[0368] Suspend 20.08 mg of Compound I in 1.0 mL of a 4 / 1 v / v mixture of IPA and H₂O. Filter the mixture, seal the filtrate in a vial with parafilm, puncture the parafilm, and allow the vial to evaporate slowly at room temperature for 8 days. The resulting solid, Form N, was collected, and its XRPD pattern is shown in Figure 12-1.

[0369] 12. Crystal Form O

[0370] 20.17 mg of amorphous Compound 1 was added to a 3 mL vial, which was then placed into a 20 mL vial containing 3 mL of acetone. The 20 mL vial was sealed with a lid and allowed to stand at room temperature to allow the acetone vapor to interact with Compound 1. The resulting solid was removed after 10 days and was Form O, whose XRPD pattern is shown in Figure 13-1.

[0371] Compared with the metastable crystal form described in Example 4, no crystalline weakness or crystal form transition was observed in the crystal form described in Example 3 under drying conditions at 50°C.

[0372] The melting points of anhydrous Form A and Form G are both over 170°C, and both exhibit excellent crystalline properties in terms of equilibrium solubility, hygroscopicity, solid-state stability, pressure stability, and high-humidity stability.

[0373] As solvates, Form C, Form O, Form E, Form Ix, Form J, Form K, Form L, Form M, Form N and Form D can all remain stable for a long time when the solvent does not evaporate at high temperatures (e.g., greater than 100°C).

[0374] Example 4: Preparation of a metastable crystalline form of Compound I

[0375] 1. Crystal Form B

[0376] 200.09 mg of amorphous Compound I was suspended in 5 mL of a mixture of CH2Cl2 / HEP (1 / 2 v / v). The suspension was magnetically stirred at room temperature for about 1 day, and then a solid was separated, which was Form B. Its XRPD pattern is shown in Figure 14.

[0377] 2. Crystal form H

[0378] 100.06 mg of Compound I was suspended in 11 mL of a 2 / 1 v / v mixture of EtOAc and HEP. The suspension was then heated to 50°C, equilibrated for approximately 2 hours, and filtered. The filtrate was slowly cooled to room temperature in a water bath. The solid was isolated to obtain Form H, whose XRPD pattern is shown in Figure 15.

[0379] 3. Crystal Form F

[0380] 100.14 mg of Compound I was added to 9.0 mL of a 2-MeTHF / HEP (8 / 1 v / v) mixture and filtered. The filtrate was sealed in a vial with parafilm, which was then punctured and allowed to evaporate slowly at room temperature for 3 days. The resulting solid was collected to obtain Form F, whose XRPD pattern is shown in Figure 16.

[0381] 4. Crystal Form P

[0382] 19.87 mg of Compound 1 was added to a 5.0 mL vial, 1.0 mL of CH2Cl2 was added, and the solution was filtered to obtain a clear solution. This solution was added to a 20 mL vial containing 3 mL of HEP, and the solid was isolated to obtain Form P, whose XRPD pattern is shown in Figure 17.

[0383] The four metastable crystalline forms described in Example 4 were less stable than the crystalline forms described in Example 3. Form B became amorphous after drying at 50°C for 3 hours, Form H became weakly crystalline after drying at 50°C for 2 hours, Form F converted to the stable Form D after being sealed in a closed container for 21 days, and Form P became amorphous after drying at 50°C for 3.5 hours.

[0384] Example 5: Equilibrium Solubility Determination of Compound I

[0385] The equilibrium solubility of Form A and Form G of Compound I was determined at 37°C for 24 hours in four media, namely H2O (purified water), FaSSGF (fasted simulated gastric fluid), FaSSIF (fasted simulated intestinal fluid) and FeSSIF (fed simulated intestinal fluid).

[0386] 10 mg of Form A and Form G were added to 1 mL of the corresponding medium and magnetically stirred at a constant temperature (37 ± 2°C). After 24 hours, samples were collected and centrifuged. The resulting solids were subjected to XRPD analysis, and the supernatant was filtered and then subjected to solubility testing.

[0387] The results shown in Table E-1 indicate that after 24 hours of stirring in various media, Form A and Form G showed no observed crystalline form change in H₂O, FeSSIF, or FaSSIF; however, hydrochloride salts were formed in FaSSGF. In water, the equilibrium solubilities of Form A and Form G were both less than 0.1 mg / mL.

[0388] Table E-1: Equilibrium Solubility of Form A and Form G of Compound I

[0389] Compared to water, Form A has significantly improved solubility in both FeSSIF and FaSSGF, which is advantageous for oral administration before or after a meal. Form G has significantly improved solubility in FeSSIF compared to water, which is advantageous for oral administration after a meal. In the case of oral administration before a meal, Form A may be more advantageous than Form G.

[0390] Example 6: Hygroscopicity Determination of Form A and Form G of Compound I

[0391] To assess the stability risk of samples at 25°C with changes in humidity, DVS testing was performed on Forms A and G of Compound I. The test results are summarized in Table E-2, the DVS spectra of Form A are shown in Figures 2-5, and the DVS spectra of Form G are shown in Figures 3-5.

[0392] Table E-2: Hygroscopicity of Form A and Form G

[0393] *: Hygroscopicity is based on the weight gain of the sample when the humidity rises to 80% RH at 25°C. 0.2%-2% is slightly hygroscopic, and 2%-15% is quite hygroscopic.

[0394] The results showed that at 80% RH, Form A absorbed 0.89% water, while Form G absorbed 0.73%, indicating that both are slightly hygroscopic. No changes in the crystal form were observed before and after the DVS test. Both Forms A and G exhibit good low hygroscopicity.

[0395] Example 7: Solid-state stability determination of Form A and Form G of Compound I

[0396] Form A and Form G of Compound I were placed under long-term (25°C / 60% RH) and accelerated (40°C / 75% RH) conditions for 10 days, and then tested for HPLC purity and crystal form change. The test results are summarized in Table E-3.

[0397] Table E-3: Solid-state stability test results

[0398] The results showed that no changes in the crystal form of Forms A and G were observed before and after testing. Form A's purity decreased by approximately 0.6% under long-term conditions and by approximately 0.8% under accelerated conditions. Form G's purity decreased by approximately 0.4% under long-term conditions and by approximately 0.4% under accelerated conditions. Both Forms A and G exhibited good solid-state stability under both long-term and accelerated conditions, with no significant difference between the two. However, Form G appeared to be less affected by the testing conditions.

[0399] Example 8: High Temperature Stability Test of Form A and Form G of Compound I

[0400] Form A and Form G of Compound I were stored at 60°C for 1 day and 10 days, respectively, and then tested for HPLC purity and crystal form change. The test results are summarized in Table E-4.

[0401] Table E-4: High temperature stability test results

[0402] The results showed that Form A's purity decreased by approximately 0.1% after one day at high temperature and by approximately 1.1% after 10 days. Form G's purity decreased by approximately 0.3% after one day at high temperature and by approximately 1.2% after 10 days. No changes in the crystal form were observed in any of the samples. Both Forms A and G exhibited good high-temperature stability, with no significant difference between the two.

[0403] Example 9: High Humidity Stability Determination of Form A and Form G of Compound I

[0404] Compound I Form A and Form G were placed under high humidity (90% RH) conditions for 1 day and 10 days, respectively, and then tested for HPLC purity and crystal form change. The test results are summarized in Table E-5.

[0405] Table E-5: High humidity stability test results

[0406] The results showed that Form A's purity decreased by approximately 0.3% after one day and by approximately 1.0% after 10 days of high humidity. Form G's purity decreased by approximately 0.1% after one day and by approximately 1.3% after 10 days of high humidity. No changes in the crystal form were observed in any of the samples. Both Forms A and G exhibited good high-humidity stability, with no significant difference between the two.

[0407] Example 10: Pressure Stability Determination of Form A and Form G of Compound I

[0408] Compound I, Form A and Form G, were subjected to HPLC testing for purity and crystal form change after being pressed at 1000 MPa for 5 minutes. The test results are summarized in Table E-6.

[0409] Table E-6: Pressure stability test results

[0410] The results showed that the purity of Form A decreased by approximately 0.7%, and the purity of Form G decreased by approximately 0.2%. No change in the crystalline form was observed in any of the samples. Form G showed better pressure stability than Form A.

[0411] The principles and embodiments of the present invention are described herein using examples. The above examples are intended to facilitate understanding of the present invention and are not intended to limit the present invention. It should be noted that those skilled in the art may make various improvements and modifications to the present invention without departing from the principles of the present invention, and such improvements and modifications also fall within the scope of the claims of the present invention.

Claims

1. A crystalline form of Compound 1, i.e., (S)-2-((4-(6-((2-fluoro-4-(oxetan-3-yl)benzyl)oxy)pyridin-2-yl)piperidin-1-yl)methyl)-1-(oxetan-2-ylmethyl)-1H-benzo[d]imidazole-6-carboxylic acid.

2. The crystalline form according to claim 1, characterized in that The crystalline form is Form A, wherein: The X-ray powder diffraction (XRPD) pattern of the crystalline form A includes diffraction peaks at the following diffraction angles (2θ): about 4.97±0.2°, 11.74±0.2°, 13.27±0.2°, 21.04±0.2° and 24.06±0.2°; and / or The differential scanning calorimetry (DSC) spectrum of the crystalline form A has a single endothermic peak at a peak value of about 177.8°C ± 3.0°C; and / or The Form A loses about 0.037% weight during heating to about 150° C.±3° C., as measured using thermogravimetric analysis (TGA); and / or The crystal form A 1 The H NMR spectra are essentially as shown in Figures 2-4; Preferably, the XRPD pattern of the crystalline form A further comprises diffraction peaks at any one, multiple or all of the following diffraction angles (2θ): about 15.88±0.2°, 16.26±0.2°, 16.44±0.2°, 18.43±0.2°, 19.17±0.2°, 19.48±0.2°, 19.65±0.2°, 19.89±0.2°, 20.11±0.2°, 20.67±0.2°, 21.27±0.2°, 22.81±0.2° and 23.4±0.2°; More preferably, the XRPD pattern of Form A further comprises diffraction peaks at any one, multiple or all of the following diffraction angles (2θ): about 9.99±0.2°, 17.65±0.2°, 20.32±0.2°, 24.26±0.2°, 24.76±0.2°, 25.79±0.2°, 26.75±0.2°, 27.47±0.2°, 28.19±0.2°, 29.38±0.2° and 29.91±0.2°; and / or The DSC spectrum of the crystalline form A is substantially as shown in Figure 2-2; and / or The TGA spectrum of the crystalline form A is substantially as shown in Figures 2-3; More preferably, the XRPD pattern of the crystalline form A includes a diffraction peak at a diffraction angle (2θ) substantially the same as that shown in Figure 2-1, and even more preferably, the XRPD pattern of the crystalline form A is shown in Figure 2-1; More preferably, the crystalline form A is not a solvate, and more preferably is an anhydrate.

3. The crystalline form according to claim 1, characterized in that The crystalline form is the Form G, wherein: The XRPD pattern of Form G includes diffraction peaks at the following diffraction angles (2θ): about 4.99±0.2°, 10.05±0.2°, 16.99±0.2°, 19.21±0.2° and 20.28±0.2°; and / or The DSC spectrum of the crystalline form G has a single endothermic peak at a peak value of about 188.3°C ± 3.0°C; and / or The Form G loses about 0.494% weight during heating to about 180°C ± 3°C, as measured using TGA; Preferably, the XRPD pattern of the crystalline form G further comprises diffraction peaks at any one, multiple or all of the following diffraction angles (2θ): about 12.33±0.2°, 15.84±0.2°, 17.34±0.2°, 17.59±0.2°, 20.67±0.2°, 21.68±0.2° and 26.59±0.2°; More preferably, the XRPD pattern of Form G further comprises diffraction peaks at any one, multiple or all of the following diffraction angles (2θ): about 12.62±0.2°, 15.00±0.2°, 18.30±0.2°, 23.88±0.2°, 24.72±0.2°, 29.12±0.2° and 33.76±0.2°; and / or The DSC spectrum of the crystalline form G is substantially as shown in Figure 3-2; and / or The TGA spectrum of the crystal form G is basically as shown in Figure 3-3; More preferably, the XRPD pattern of the crystalline form G includes a diffraction peak at a diffraction angle (2θ) substantially the same as that shown in FIG3-1 , and even more preferably, the XRPD pattern of the crystalline form G is shown in FIG3-1 ; More preferably, the crystalline form G is not a solvate, and more preferably is an anhydrate.

4. A pharmaceutical composition comprising the crystalline form according to any one of claims 1 to 3 and a pharmaceutically acceptable carrier, in: Preferably, the crystalline form is Form A according to claim 2, or Form G according to claim 3.

5. The crystalline form according to any one of claims 1 to 3, or the pharmaceutical composition according to claim 4, for use in the treatment and / or prevention of GLP-1 receptor-mediated diseases and related conditions. in: Preferably, the crystalline form is Form A according to claim 2, or Form G according to claim 3.

6. Use of the crystalline form according to any one of claims 1 to 3 or the pharmaceutical composition according to claim 4 in the preparation of a medicament for treating and / or preventing GLP-1 receptor-mediated diseases or related conditions, in: Preferably, the crystalline form is Form A according to claim 2, or Form G according to claim 3.

7. A method for treating and / or preventing a GLP-1 receptor-mediated disease or related condition, comprising administering to a subject in need thereof an effective amount of the crystalline form according to any one of claims 1 to 3, or the pharmaceutical composition according to claim 4, in: Preferably, the crystalline form is Form A according to claim 2, or Form G according to claim 3.

8. The crystalline form or pharmaceutical composition of claim 5, the use of claim 6, or the method of claim 7, wherein the GLP-1 receptor-mediated disease or related condition is selected from the group consisting of diabetes, hyperglycemia, insulin resistance, glucose intolerance, diabetic nephropathy, diabetic neuropathy, diabetic retinopathy, adipocyte dysfunction, obesity, non-alcoholic fatty liver disease, dyslipidemia, and hyperinsulinemia; Preferably, the diabetes is selected from: T1D and / or T2DM, idiopathic T1D, early-onset T2D, latent autoimmune diabetes, juvenile atypical diabetes and gestational diabetes.

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